In our U.S. Pat. Nos. 3,773,925 and 3,780,173, we have described and claimed a new antibiotic, which we have called partricin, and its methyl ester.
Partricin is a polyenic antibiotic and, more precisely, is a heptaenic substance which can be obtained by fermentation of a new strain of Streptomyces aureofaciens, filed at the United States Department of Agriculture, Agricultural Research Services, Northern Utilisation Research and Development Division, Peoria (USA), which has been assigned the number NRRL 3878. This antibiotic exhibits a marked antifungal activity, particularly against certain pathogenic strains of Candida albicans, and also has a marked anti-protozoal activity, especially against Trichomonas vaginalis.
The partricin methyl ester is obtained by treating a solution of partricin in an appropriate organic solvent with a slight excess of diazomethane, in order to prevent the possible formation of products with higher degrees of reaction, and then leaving the reaction mixture to stand for a few hours (or at least until the evolution of nitrogen has ceased, this being proof that the reaction has taken place). The reaction product is then precipitated by adding an appropriate solvent. This semi-synthetic antibiotic, partricin methyl ester, also exhibits a marked antifungal activity, especially against certain pathogenic strains of Candida albicans and against protozoa, i.e. Trichomonas. It also has the advantage over the parent antibiotic, partricin, of having a reduced degree of toxicity.
Both these antibiotics are, however, practically insoluble in water; in our above-mentioned United States Patent Specifications, in relation to the toxocological properties of partricin and methyl partricin, we mentioned their therapeutic use for many human and animal diseases caused by fungi and protozoa. We described the use of these antibiotics by topical application in the form of ointments, liniments or creams for dermatological purposes, or in the form of inserts or suppositories (effervescent or ordinary) for endovaginal use against mycoses and protozoal infections. Furthermore, because of their low solubility in water, we indicated, for general use, the administration thereof by the oral route only for combating mycotic or protozoal intestinal infections: since these antibiotics are not absorbed, they can only exert their activity in the intestines.
Literature, however, amply describes infections of a generalised mycotic or protozoal type (for example pulmonary mycosis) in which, obviously, administration by the topical route would be ineffective.
The two new polyenic antibiotics have a good solubility in dimethyl sulphoxide, dimethyl acetamide and pyridine (i.e. in solvents not used in the therapeutic field for parenteral administration), whereas they are practically insoluble in water and in the common organic solvents. As we have already mentioned, their insolubility in water constitutes a marked limitation.
Therefore, it is an object of the present invention to render partricin and partricin methyl ester water-soluble so as to permit administration thereof by the parenteral or oral route and to guarantee blood antibiotic levels which are high enough to combat generalised mycotic or protozoal infections. Furthermore, this water-solubilisation is to be obtained without impairing the anti-fungal and antiprotozoal activity of partricin and methyl partricin.
During our researches we have found that certain anionic and cationic surfactants, for example the nontoxic salts of sulphated aliphatic hydrocarbons, such as sodium lauryl sulphate and sodium tetradecyl sulphate, as well as benzalkonium chlorides and the like are able to make partricin, as well as partricin methyl ester, soluble in water. Of all the surfactants which we have tested, sodium lauryl sulphate shows the best water-solubilising properties.